Onapristone (ONA) is an anti-progestin drug and progesterone receptor antagonist which was originally developed for contraceptive use. However, it has demonstrated substantial activity in advanced breast cancer. While onapristone has previously been investigated as a potential therapeutic agent for breast cancer, its development was stopped due to toxicity concerns. Robertson et al., Onapristone, a Progesterone Receptor Antagonist, as First-line Therapy in Primary Breast Cancer European J. of Cancer 35(2) 214-218 (1999). It is thought that ONA binds to the progesterone receptor (PR), preventing the PR from binding to DNA and thereby inhibiting or eliminating PR-induced transcription. See, e.g., Klijn et al., Progesterone antagonists and progesterone receptor modulation in the treatment of breast cancer, Steroids, v. 65, pp. 825-830 (2000); Jonatt et al., The clinical efficacy of progesterone antagonists in breast cancer, Endocrine Therapy of Breast Cancer, pp. 117-124.
Onapristone is known to be an amorphous compound. For example, (3-Acyloxypropyl)-derivatives of Onapristone are crystalline in comparison to the parent compound. Neef, G.; Wiechert, R.; Beier, S.; Elger, W.; Henderson, D. UP 4,780461, 1988. Onapristone has previously been isolated as an amporphous solid and as a yellow oil. Neef, G.; Wiechert, R.; Beier, S.; Elger, W.; Henderson, D. Steroids, 1984, 44, 349; Neef, G Sauer, G.; Wiechert, R.; Beier, S.; Elger, W.; Henderson, D.; Rohde, R. DE3321826, 1984.
The term “polymorph” or “polymorphic” refers to different crystalline forms of a chemical compound. Polymorphic or crystalline forms of a compound may possess properties that affect the solubility, stability, bioavailability, and efficacy of a compound. Polymorphic forms of a compound can be compared, for example, to amorphous forms or other crystalline forms with respect to thermodynamic behaviors measured by a variety of techniques including, but not limited, to melting point, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), high performance liquid chromatography (HPLC), Raman microscopy, FT-IR spectroscopy, mass spectrometry (MS), and thermogravimetric analysis coupled with mass spectrometry (TG-MS). The physical stability of crystalline forms can be measured, for example, under conditions where the temperature and humidity in the environment are controlled for various time periods.